Next-generation sequencing for myeloid malignancies
Progress and practical applications
DOI:
https://doi.org/10.58931/cht.2022.115Abstract
Over the past two decades, next-generation sequencing (NGS) has revolutionized our understanding of the pathogenesis of myeloid neoplasms (MNs) and their clinical management. While traditional Sanger sequencing allows for the interrogation of single loci, NGS enables the parallel sequencing of multiple genomic locations, ranging from targeted sets of genes to the entire genome. Initially, NGS was used predominantly in research, where the ability to interrogate large regions of the genome facilitated the discovery of genes recurrently mutated in myeloid malignancies. Soon thereafter, NGS entered the clinical realm where it is now routinely utilized in diagnosis, prognostication and treatment decision-making. However, the broad availability of clinical NGS comes with a unique set of challenges. Hematologists must interpret complex molecular reports and appropriately apply the provided mutational information to their patients’ care in real-time. Consequently, a systematic approach to interpreting NGS reports is crucial; the following will outline one such framework.
References
Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2017;17(1):5-19. doi:10.1038/nrc.2016.112 DOI: https://doi.org/10.1038/nrc.2016.112
Kennedy JA, Ebert BL. Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(9):968-974. doi:10.1200/JCO.2016.71.0806 DOI: https://doi.org/10.1200/JCO.2016.71.0806
McClure RF, Ewalt MD, Crow J, et al. Clinical Significance of DNA Variants in Chronic Myeloid Neoplasms: A Report of the Association for Molecular Pathology. J Mol Diagn JMD. 2018;20(6):717-737. doi:10.1016/j.jmoldx.2018.07.002 DOI: https://doi.org/10.1016/j.jmoldx.2018.07.002
Lindsley RC, Saber W, Mar BG, et al. Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med. 2017;376(6):536-547. doi:10.1056/NEJMoa1611604 DOI: https://doi.org/10.1056/NEJMoa1611604
Feurstein S, Drazer M, Godley LA. Germline predisposition to hematopoietic malignancies. Hum Mol Genet. 2021;30(20):R225-R235. doi:10.1093/hmg/ddab141 DOI: https://doi.org/10.1093/hmg/ddab141
Ferrone CK, Wong H, Semenuk L, et al. Validation, Implementation, and Clinical Impact of the Oncomine Myeloid Targeted-Amplicon DNA and RNA Ion Semiconductor Sequencing Assay. J Mol Diagn JMD. 2021;23(10):1292-1305. doi:10.1016/j.jmoldx.2021.07.010 DOI: https://doi.org/10.1016/j.jmoldx.2021.07.010
Li MM, Datto M, Duncavage EJ, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn JMD. 2017;19(1):4-23. doi:10.1016/j.jmoldx.2016.10.002 DOI: https://doi.org/10.1016/j.jmoldx.2016.10.002
den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat. 2016;37(6):564-569. doi:10.1002/humu.22981 DOI: https://doi.org/10.1002/humu.22981
Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-443. doi:10.1038/s41586-020-2308-7 DOI: https://doi.org/10.1530/ey.17.14.3
DiNardo CD, Routbort MJ, Bannon SA, et al. Improving the detection of patients with inherited predispositions to hematologic malignancies using next-generation sequencing-based leukemia prognostication panels. Cancer. 2018;124(13):2704-2713. doi:10.1002/cncr.31331 DOI: https://doi.org/10.1002/cncr.31331
Bacher U, Shumilov E, Flach J, et al. Challenges in the introduction of next-generation sequencing (NGS) for diagnostics of myeloid malignancies into clinical routine use. Blood Cancer J. 2018;8(11):113. doi:10.1038/s41408-018-0148-6 DOI: https://doi.org/10.1038/s41408-018-0148-6
Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019;47(Database issue):D941-D947. doi:10.1093/nar/gky1015 DOI: https://doi.org/10.1093/nar/gky1015
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544 DOI: https://doi.org/10.1182/blood-2016-03-643544
MarnethAE,MullallyA.TheMolecularGeneticsof Myeloproliferative Neoplasms. Cold Spring Harb Perspect Med. 2020;10(2):a034876. doi:10.1101/cshperspect.a034876 DOI: https://doi.org/10.1101/cshperspect.a034876
Papaemmanuil E, Cazzola M, Boultwood J, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365(15):1384-1395. doi:10.1056/NEJMoa1103283 DOI: https://doi.org/10.1056/NEJMoa1103283
Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289-2301. doi:10.1056/NEJMoa0810069 DOI: https://doi.org/10.1056/NEJMoa0810069
Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472-1478. doi:10.1038/nm.3733 DOI: https://doi.org/10.1038/nm.3733
Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477-2487. doi:10.1056/NEJMoa1409405 DOI: https://doi.org/10.1056/NEJMoa1409405
Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498. doi:10.1056/NEJMoa1408617 DOI: https://doi.org/10.1056/NEJMoa1408617
Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16. doi:10.1182/blood-2015-03-631747 DOI: https://doi.org/10.1182/blood-2015-03-631747
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. doi:10.1182/blood-2016-08-733196 DOI: https://doi.org/10.1182/blood-2016-08-733196
Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-1869. doi:10.1038/leu.2013.119 DOI: https://doi.org/10.1038/leu.2013.119
Tefferi A, Finke CM, Lasho TL, et al. U2AF1 mutation types in primary myelofibrosis: phenotypic and prognostic distinctions. Leukemia. 2018;32(10):2274-2278. doi:10.1038/s41375-018-0078-0 DOI: https://doi.org/10.1038/s41375-018-0078-0
Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(4):310-318. doi:10.1200/JCO.2017.76.4886 DOI: https://doi.org/10.1200/JCO.2017.76.4886
Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(17):1769-1770. doi:10.1200/JCO.2018.78.9867 DOI: https://doi.org/10.1200/JCO.2018.78.9867
Nazha A, Komrokji R, Meggendorfer M, et al. Personalized Prediction Model to Risk Stratify Patients With Myelodysplastic Syndromes. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(33):3737-3746. doi:10.1200/JCO.20.02810 DOI: https://doi.org/10.1200/JCO.20.02810
Bersanelli M, Travaglino E, Meggendorfer M, et al. Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes. J Clin Oncol. 2021;39(11):1223-1233. doi:10.1200/JCO.20.01659 DOI: https://doi.org/10.1200/JCO.20.01659
Bernard E. Molecular International Prognosis Scoring System for Myelodysplastic Syndromes. In: ASH; 2021. Accessed February 12, 2022. https://ash.confex.com/ash/2021/webprogram/Paper150554.html
Bernard E, Nannya Y, Hasserjian RP, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26(10):1549-1556. doi:10.1038/s41591-020-1008-z DOI: https://doi.org/10.1038/s41591-020-1008-z
Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178-184. doi:10.1038/nm.3788 DOI: https://doi.org/10.1038/nm.3788
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971 DOI: https://doi.org/10.1056/NEJMoa2012971
Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-2145. doi:10.1182/blood.2020004856 DOI: https://doi.org/10.1182/blood.2020004856
Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25(7):1147-1152. doi:10.1038/leu.2011.71 DOI: https://doi.org/10.1038/leu.2011.71
Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124(17):2705-2712. doi:10.1182/blood-2014-06-582809 DOI: https://doi.org/10.1182/blood-2014-06-582809
Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28(1):78-87. doi:10.1038/leu.2013.269 DOI: https://doi.org/10.1038/leu.2013.269
Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359 DOI: https://doi.org/10.1056/NEJMoa1614359
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688 DOI: https://doi.org/10.1056/NEJMoa1902688
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405 DOI: https://doi.org/10.1182/blood-2017-04-779405
DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984 DOI: https://doi.org/10.1056/NEJMoa1716984
Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(14):1584-1594. doi:10.1200/JCO.20.02341 DOI: https://doi.org/10.1200/JCO.20.02341
Lee SCW, Dvinge H, Kim E, et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med. 2016;22(6):672-678. doi:10.1038/nm.4097 DOI: https://doi.org/10.1038/nm.4097
Steensma DP, Wermke M, Klimek VM, et al. Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia. 2021;35(12):3542-3550. doi:10.1038/s41375-021-01328-9 DOI: https://doi.org/10.1038/s41375-021-01328-9
Niemeyer CM, Kang MW, Shin DH, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9):794-800. doi:10.1038/ng.641 DOI: https://doi.org/10.1038/ng.641
Tefferi A, Nicolosi M, Mudireddy M, et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia. 2018;32(5):1189-1199. doi:10.1038/s41375-018-0018-z DOI: https://doi.org/10.1038/s41375-018-0018-z
